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WO1993008122A1 - Agents et compositions de contraste pour l'imagerie radiologique, et procede d'imagerie radiologique faisant appel a ces compositions et agents - Google Patents

Agents et compositions de contraste pour l'imagerie radiologique, et procede d'imagerie radiologique faisant appel a ces compositions et agents Download PDF

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Publication number
WO1993008122A1
WO1993008122A1 PCT/US1992/009120 US9209120W WO9308122A1 WO 1993008122 A1 WO1993008122 A1 WO 1993008122A1 US 9209120 W US9209120 W US 9209120W WO 9308122 A1 WO9308122 A1 WO 9308122A1
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Prior art keywords
boron
groups
formula
contrast agent
iodine
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PCT/US1992/009120
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English (en)
Inventor
Dominique Meyer
Bernard F. Spielvogel
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Guerbet SA
Boron Biologicals Inc
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Guerbet SA
Boron Biologicals Inc
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Priority to JP5507942A priority Critical patent/JPH07502991A/ja
Priority to EP92923022A priority patent/EP0609374A4/fr
Priority to IL103696A priority patent/IL103696A0/xx
Publication of WO1993008122A1 publication Critical patent/WO1993008122A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5355—Phosphoranes containing the structure P=N-
    • C07F9/5357—Polyphosphazenes containing the structure [P=N-]n
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B35/00—Boron; Compounds thereof
    • C01B35/06—Boron halogen compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/062—Organo-phosphoranes without P-C bonds
    • C07F9/065—Phosphoranes containing the structure P=N-
    • C07F9/067—Polyphosphazenes containing the structure [P=N-n]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/65812—Cyclic phosphazenes [P=N-]n, n>=3
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule

Definitions

  • This invention variously relates to contrast agents for X- ray imaging, a method of imaging a visualizable corporeal situs by radiological imaging techniques (comprising delivery to the situs of an imagingly effective amount of an imagingly effective, physiologically acceptable contrast agent) , and contrast media formulations useful for such imaging.
  • radiological imaging reagents are employed. These reagents comprise contrast agents which typically are administered in compositions or formulations to the patient or subject, for delivery to the corporeal situs part of the body) to be visualized. After administration to the body, the corporeal region to be visualized is subjected to radiation (e.g. . X-ray) exposure and fluoroscopic analysis.
  • radiation e.g. . X-ray
  • radiological reagents are delivered to a coronary situs in coronary angioplasty by means of an angiographic syringe or injector, which directs the contrast media through a catheter or other passage means into the appropriate coronary lumen.
  • contrast agents e.g., coronary angioplasty or injector
  • imaging reagent may be transcervically introduced by a syringe, pump, or injector, following which the pelvic region is radiologically visualized.
  • Contrast media reagents comprise a constituent imparting radiopacity thereto, typically an iodine-based compound which is physiologically acceptable, e.g., organically-bound iodine.
  • iodine-based radiological imaging reagents include the iodine-based radiopaque contrast medium formulation which is commercially available under the trademark VASCORAY® from Mallinckrodt Corporation (St. Louis, Missouri, USA).
  • X-ray contrast agents already known in the art include a number of halogenated derivatives, especially iodinated derivatives, of 5-amino-isophthalic acid, e.g., the halogenated derivatives described in French Patent No. 2 053 037.
  • the contrast medium must be completely removed (flushed, or otherwise extracted) from the corporeal system following visualization of the desired situs.
  • the active ingredient of conventional iodine-based imaging formulations frequently has a relatively low concentration or "loading" of iodine associated therewith, as a result of which relatively high dosages of the contrast medium are required.
  • the active ingredients employed in many radiological imaging formulations frequently are poorly soluble in the carrier medium of the formulation.
  • a superior radiological imaging reagent which (1) is physiologically acceptable, (2) is safe, highly effective, and efficient in character, e.g., at relatively low dosage, (3) comprises an active ingredient which is water soluble so that water may be employed as the solvent medium of the reagent formulation, (4) is excreted in normal functioning of the corporeal system, and (5) produces (aqueous) formulations characterized by low osmolality and low viscosity.
  • relevant art comprises the aforementioned French Patent 2 053 037 and the art which is described below.
  • U.S. Patent 4,713,235 to R. E. Krall discloses organic iodo agents, particularly iodo carboxylic acids, as radiopaque agents in acrylate-based occlusion compositions for female sterilization.
  • the iodine reagents are discussed at column 3, line 20 to column 4, line 22 of the patent.
  • a diagnostic radiopaque formulation is commercially available from Mallinckrodt, Inc. (St. Louis, MO) under the trademark VASCORAY®.
  • This contrast media formulation is a phosphate-buffered solution containing organically bound iodine.
  • the present invention relates to a contrast agent which is constituted by a halogenated, especially
  • Such contrast agent may for example comprise a halogenated derivative of boron, e.g., an organic halogenated derivative of boron, which is characterized by: a stability in water sufficiently high to enable it to withstand sterilization conditions; a high molar halogen concentration, especially iodine or bromine concentration, equal to at least 10%, preferably to at least 30% and, still more preferably, to at least 40%, and lower than 95%, a low osmolality, lower than 2000 mosmol/kg H 2 O,
  • a halogenated derivative of boron e.g., an organic halogenated derivative of boron, which is characterized by: a stability in water sufficiently high to enable it to withstand sterilization conditions; a high molar halogen concentration, especially iodine or bromine concentration, equal to at least 10%, preferably to at least 30% and, still more preferably, to at least 40%, and lower than 95%, a low osmolality, lower than 2000 mosmol
  • concentrations i.e., higher than 100 g of halogen, especially of iodine or of bromine per liter; and a low toxicity
  • a LD 50 intravenously in mouse higher or equal to 2 g of halogen, especially of iodine or bromine, per kg of body weight of a mouse test subject.
  • the present invention relates to a method of radiologically visualizing a corporeal situs. comprising delivery to the situs of an imagingly effective amount of a physiologically acceptable contrast medium formulation comprising a radiopacity-imparting boron compound, followed by visualizing the corporeal situs with radiological imaging means.
  • the term “physiologically acceptable” means that the contrast medium is biocompatible in character, with respect to its administration, contact, and action in the corporeal system with which the contrast medium is used.
  • imagingly effective means efficacious for radiological imaging using a radiation source and visualizing means, e.g., X-ray source and fluoroscopic visualizing means.
  • boron compound is intended to be broadly construed to encompass a wide variety of boron derivatives, and to include (i) compounds per se, (ii) ionic (anionic, cationic, zwitterionic) or non-ionic moieties, and/or (iii) coordinating complexes containing at least one boron atom as a constituent thereof.
  • a "halogenated boron compound” is a boron compound having halogen atoms or ions in the boron compound as constituents thereof.
  • the halogen, or halo, moiety may suitably comprise fluorine, chlorine, bromine, and/or iodine, and in a preferred aspect, the halogenated boron compound contains iodine or bromine.
  • Suitable halogen-containing boron compounds may be obtained from polyboranes (see Chemical Reviews 92, 2, 177-362, 1992).
  • the boron compounds of the invention for use as contrast agents include halogenated, especially iodinated or brominated, organic derivatives of boron, of the formula:
  • n is an integer from 3 to 14, preferably from 9 to 12
  • m is an integer from 0 to 2
  • y is an integer from 1 to 14, preferably 1 to 12,
  • x is an integer from 0 to 4,
  • M is the mono- or multivalent cation of an orgainc
  • X is substituents, identical to or different from one another, selected from among:
  • Y halogen or NR 1 R 2 , in which R 1 and R 2 are selected from hydrogen, alkyl groups in C 1 to C 12 , preferably in C 1 to C 4 , linear, branched, or cyclic hydroxyalkyl and polyhydroxyalkyl in C 1 to C 10 , preferably in C 1 to C 6 , linear or branched alkoxy groups especially in C 1 to C 6 , and linear or branched polyhydroxy alkoxy groups in C 1 to
  • halogenated boron compounds may be employed comprising a polyphosphazene or other inorganic polymer, as a backbone structure to which halogen-containing moieties are pendently bonded or otherwise associated.
  • polymeric halogen-containing boron compounds comprise functional groups imparting water solubility to the polymer, and most preferably, the polymer comprises functionality which imparts water solubility as well as hydrolytic character, whereby the polymer may be degraded in vivo, e . g . , to physiologically acceptable hydrolysis reaction products which are readily bioassimilated by and /or excreted from the corporeal system.
  • the present invention relates to various other specific novel boron compounds , as hereinafter disclosed in detail, having application in contrast media of the invention, e . g. , as an active ( radiopacity-imparting) ingredient in a contrast medium formulation.
  • the novel diagnostic imaging compositions include various contrast agents in "vectorized” form, wherein the contrast agent is associated with a biocompatible "carrier” entity, which may for example comprise an encapsulant such as a liposome, or a macromole ⁇ ule or polymer to which the contrast agent is fixed or bonded.
  • a biocompatible "carrier” entity which may for example comprise an encapsulant such as a liposome, or a macromole ⁇ ule or polymer to which the contrast agent is fixed or bonded.
  • Still other aspects of the invention include methods of making various specific imaging compounds , as hereinafter more fully described.
  • the present invention is based on the surprising and unexpected discovery that useful contrast media reagents may be based on boron compounds , including boron compounds known heretofore e.g. , iodine-containing borohydride compounds and derivatives , as well as novel boron compounds hereinafter more fully described.
  • contrast agents consisting of halogenated, especially iodinated or brominated, organic derivatives of boron of the formula:
  • n is an integer from 3 to 14, preferably from 9 to 12
  • m is an integer from 0 to 2
  • y is an integer from 1 to 14, preferably from 1 to 12, x is an integer from 0 to 4,
  • M is the mono- or multivalent cation of an orgainc
  • X is substituents, identical to or different from one another, selected from among:
  • Y halogen or NR 1 R 2 , in which R 1 and R 2 are selected from hydrogen, alkyl groups in C 1 to C 12 , preferably in C 1 to C 4 , linear, branched, or cyclic hydroxyalkyl and polyhydroxyalkyl in C 1 to C 6 , linear or branched alkoxy groups especially in C 1 to C 6 ,
  • boron compounds potentially useful as contrast agents in the practice of the invention comprises halogenated (iodinated) salts of borohydrides, particularly iodinated boron salts of the formula:
  • M is a monovalent or divalent cation, preferably an alkali metal or alkaline earth metal
  • x is 1 when M is divalent and 2 when M is monovalent;
  • n 3 to 14, preferably 10 to 12;
  • y is 1 to 14, preferably 2 to 12,
  • Another class of potential contrast agents includes polyphosphazene boron compounds , including polyphosphazenes of the following formula:
  • a 1 , and A 2 are end groups independently selected from hydrogen, halo, and organo which preferably are of a suitable organic constituency which is compatible with the polyphosphazene and does not preclude its efficacy for radiological imaging purposes -
  • a 1 and A 2 may be the same or dif ferent , and may for example comprise alkyl or other hydrocarbyl radicals;
  • R 1 and R 2 may be the same or different , and are independently selected from hydrogen , halo, and organo groups (e. g. , alkyl , haloalkyl , aryl , arylalkyl, alkenyl , alkylamino, arylamino, etc.
  • organo groups e. g. , alkyl , haloalkyl , aryl , arylalkyl, alkenyl , alkylamino, arylamino, etc.
  • R 1 and R 2 groups comprises at least one halogen atom and at least one boron atom (e.g., halogen and boron atoms may be present as R 1 and/or R 2 substituents on a single phosphorus atom of the polymer, or on more than one phosphorus atom (repeating unit) of the polymer, and which are of a suitable radiopaque character.
  • R 1 and R 2 are the same as above, and the compound is subject to the same proviso and radiopacity criterion as stated above, and n is from 3 to 8.
  • At least one of the R 1 and R 2 groups comprises functionality (e.g., -NH(CH 3 ) groups) imparting water solubility to the polyphosphazene or cyclophosphazene, as the case may be.
  • functionality e.g., -NH(CH 3 ) groups
  • the R 1 group in a first repeating unit or moiety of the phosphazene compound may be the same as or different from the R 1 group in the next and other repeating units/moieties in the phosphazene compound.
  • the R 1 and R 2 groups joined to each of the phosphorous atoms in the compound may differ independently from one another, or, alternatively, all of the individual R 1 and R 2 groups, each of which is independently selected relative to the other, may be the same on the respective phosphorous atoms.
  • the contrast agent according to the invention comprising a halogenated, preferably iodinated or brominated, derivative of boron, e.g., an organic derivative of such type, advantageously possesses the following characteristics for its use in X-ray imaging:
  • a high molar halogen concentration especially iodine or bromine concentration, equal to at least 10%, preferably to at least 30% and, still more preferably, to at least
  • Physiologically acceptable salts of contrast agents according to the invention include the salts of meglumine (or Mgl), lysine (or Lys), arginine (or Arg), sodium, potasium, ammonium, calcium, and N-methyl-glucamine salts of the polyiodinated anions corresponding to the formulas B 12 l 12 2- and B 10 l 10 2- , i.e.:
  • the present invention also comprehends the isomers of the derivatives of formula (I), especially the position isomers, the sterioisomers under optically active or racemic form.
  • [B 12 I 10 (OCH 3 )2] 2 - and [B 10 I 8 (OCH 3 ) 2 ] 2 - can be prepared by use of the processes disclosed in JACS, Vol. 86, pages 3973-3983 (1964).
  • [B 12 l 10 (NHCOCH 3 ) 2 ] 2 - and [B 10 l 8 (NHCOCH 3 ) 2 ] 2 - can be prepared by use of the processes disclosed in JACS, Vol. 88, pages 935-939 (1966).
  • halogenation techniques especially iodation used for the preparation of the contrast agents according to the invention, are carried out in the presence of iodine and/or ICl, using the process disclosed in "Inorg.Chem.”, Vol. 3, pages 159-167 (1964).
  • the preferred contrast agents according to the invention present particular features which are associated with their chemical structure and as a result of which they are especially adapted to x-ray imaging applications, especially a high stability and a concentration in radioopaque halogen atoms which is especially high when compared with the concentration in halogen atoms of the polyiodinated compounds conventionally used as contrast agents in the field of X-ray imaging.
  • a useful contrast medium formulation typically comprises the active ingredient (i.e., the radiopaque boron compound) together with one or more physiologically acceptable carriers thereof and optionally any other therapeutic or desired ingredients.
  • the carrier(s) must be physiologically acceptable in the sense of being compatible with the other ingredients of the formulation and not unsuitably deleterious to the recipient thereof.
  • the active agent ingredient is provided in an amount effective to achieve the desired radiopacity and radiological imaging effect, and in a quantity appropriate to such purpose.
  • An X-ray imaging composition according to the invention may therefore include at least one above-mentioned contrast agent in an aqueous solution or suspension, preferably in bidistillated water; the composition alternatively may be in the form of a powder.
  • a radiological imaging contrast medium formulation of the present invention may comprise a sterile aqueous solution, for intravascular administration, as the diagnostic radiopaque medium employed in excretory urography, angiocardiography, or aortography, or in other contrast medium application.
  • the contrast medium formulation may usefully include adjuvants generally used in pharmaceutical compositions containing contrast agents, such as salts and buffers rendering the sterile aqueous solution isotonic with the receiving locus of the corporeal system to which the contrast medium formulation is administered.
  • adjuvant ingredients may include calcium disodium, monobasic sodium phosphate, sodium chloride, tris (hydroxymethyl)amino-methane hydrochloride, amine of (trishydroxymethyl)amino-methane, heparine, sodium citrate, and sodium calciedetate.
  • At least 15% by volume, based on the total volume of solution, of the formulation is chemically bound iodine deriving from boron compounds of the present invention, preferably at least 40%, and most preferably at least 50%, of iodine, on such volume basis.
  • the concentration desirably is from about 0.05 M to about 1 M, preferably from about 0.2 M to about 0.5 M per liter.
  • the contrast medium reagent formulation of the present invention may include salts, buffers, diluents, binders, disintegrants, surface active agents, thickeners, preservatives (including anti- oxidants), etc.
  • the administration of the boron compound-containing contrast medium formulation to the corporeal situs to be visualized may be carried out in any suitable manner and with any efficacious means and methods.
  • the intravascular administration of contrast medium formulation may be effected by a catheter joined at one end to a vascular locus and in fluid introduction relationship therewith.
  • the other end of the catheter may be joined to a suitable angiographic syringe, such as a Coeur 150 ml angiographic syringe, commercially available from Coeur Laboratories, Inc. (Raleigh, North Carolina, USA), as employed in a Medrad Mark V® angiographic injector, commercially available from Medrad, Inc. (Pittsburgh, Pennsylvania, USA).
  • the dosage of the contrast medium formulation in the administration of the formulation to the corporeal situs, may be at any suitable level consistent with the imaging function to be carried out.
  • a formulation containing approximately 40% chemically bound iodine deriving from boron compound(s) therein may be usefully employed for urographic, angiocardiographic, and/or aortographic applications, at an intravenous dosage in adults of 25-50 ml of the formulation, injected over a period of 15-120 seconds, and more preferably over a period of 30-90 seconds, so that peak blood values are obtained immediately following injection, and equilibration with extracellular compartments is attained in approximately 5- 15 minutes.
  • compositions containing X- ray contrast agents according to the invention may be administered with a useful dose from about 10 to about 250 ml of aqueous solution containing from about 100 to about 500 g of halogen per liter, preferably from about 200 to about 400 g of halogen per liter.
  • Administration of the X-ray contrast agent formulation may be enterally or parenterally, especially orally, rectally, intraveneously, intra-articularly, intra-arterially, sub- arachnoidly as well as bronchially, lymphatically and intra- uterinally.
  • the composition can be administered enterally, orally, rectally or bronchially.
  • the X-ray contrast agent formulation according to the invention is in the form of a colloidal suspension, it suitably comprises the iodinated derivatives of boron in the form of insoluble particles of a size lower than 1 micron and preferably lower than 400 nm, suspended in physiologically compatible solvent, preferably aqueous medium such as water, to carry out X-ray imaging of the vascular sector, of the liver, and of the lymphatic ganglions.
  • physiologically compatible solvent preferably aqueous medium such as water
  • an insoluble salt of B 10 I 10 2- may be provided in an aqueous suspension of 300 nm average diameter particles of the salt, at a salt concentration providing the requisite bioavailability in vivo.
  • compositions according to the invention comprising the aforementioned contrast agents present especially advantageous osmolatities; for example, the dose of 35 g of iodine per 100 ml which is generally used in X-ray imaging is obtained, as long as a triiodinated compound of the prior art is used, with a solution whose concentration is about 0.9 M, while it proves sufficient to use the solution based on a contrast agent according to formula (I) at a molar concentration from three to four times lower.
  • N-methylglucamine 9.75 g (0.5 M) water for an injectable preparation q.s.p. 100 ml b) B 10 I 10 2- 34.5 g (0.25 M)
  • N-methylglucamine 4.88 g (0.25 M) water for an injectable preparation q.s.p. 100 ml c) B 12 I 10 (OCH 3 ) 2 2- 36.5 g (0.25 M)
  • the pH of the above-mentioned solutions is suitably adjusted to a value between about 6.5 and about 7.5.
  • a vectorisation of the contrast agent which can be obtained for example by encapsulation of the agent within liposomes, or by its fixation or bonding on a macromolecule, polymer, mi ⁇ rosphere (e.g., microbead), or other “anchoring" or “carrier” moiety.
  • the macromolecules adapted to be used in connection with such a use may be of biological or synthetic origin and especially selected among proteins, polyalkyamines, liopoproteins, glycoproteins, polysaccharides and polypeptides; for example, use can be made, as macromolecules of the kind in question, of starches, hydroxyethyl starches, arabinogalactans, dextrans, polylysins, albumin, poly and monoclonal antibodies, and star-shaped polymers called "dendrimers" (preferably polymers of such type having a weight average molecular weight in the range of from about 1000 to about 100,000 daltons).
  • activated dextran with NaI04 can react with an iodinated boron derivative comprising at least one group X equal to NH 2 in the presence of sodium cyanoborohydride.
  • the residual aldehydes are reduced using sodium borohydride and the resultingly obtained polymer is purified by way of dialysis.
  • the pathologies whose diagnosis can be facilitated by way of such a vectorisation are especially tumoral pathologies, liver pathologies, and distribution abnormalities of the blood volume.
  • compositions, dosage, and administration parameters are illustrative in character, and that the composition, dosage, and administration techniques may be varied widely in the broad practice of the present invention, within the skill of the relevant art.
  • the icosahedral B 12 framework provides the basis for an entirely new generation of contrast media agents.
  • the properties of the parent moiety, B 12 H 12 2- will be briefly described below, followed by a description of various halogenated (iodinated) species based on same.
  • CS 2 B 12 H 12 can be heated to 810°C in an evacuated sealed quartz tube and recovered unchanged. It is also quite thermally stable in air. b. Hydrolytic Stability
  • B 12 H 12 2- salts show no reaction with strong aqueous sodium hydroxide even at 95°C.
  • B 12 H 12 2- is stable to 3N HCl at 95°C. c. Solubility
  • the approximate lethal dose of Na 2 B 12 H 12 , administered orally to rats, is greater than 7.5 gm/kg of body weight. This is approximately equal to the oral toxicity of sodium chloride.
  • Massive doses of a closely related derivative, Na 2 B 10 H 10 have been given to humans without serious effect and the anion recovered from urine specimens. Such biological inertness is attributed to its chemical stability.
  • the twelve boron atoms in the B 12 H 12 2- anion have icosahedral symmetry, and each boron atom has an exopolyhedral hydrogen bond.
  • the volume of the B 12 H 12 2- ion is comparable to that swept out by a rotating benzene group. f. Cost
  • Na 2 B 12 l 12 has an unexpectedly high solubility in water. d. Preparation
  • the first two iodine atoms can be placed on the icosahedral cage by reaction of I 2 in accordance with the equation:
  • Table I presents molecular weight data on some B 12 H 12 2- salts and iodinated derivatives and the % iodine in the latter. Table I Molecular Weight of B 12 H 12 2- Salts,
  • X-ray contrast agent formulations already known in the art are characterized by high viscosity, typically between 5 to 20 mpasc . s at 37°C and at 32g iodine/100 cm 3 of solution. f. Osmolality Considerations
  • X-ray contrast agents based upon polyiodinated benzene derivatives are customarily formulated such that 100 cm 3 of sterile solution containing 32 grams of iodine ( 60 grams of whole product ) are injected . This represents a water solubility of about 1M.
  • osmolality is proportional to the number of dissolved particles , a 0.21 M solution of Na 2 B 12 l 12 would (ideally) behave as a 0.63 M solution of a non-ionic contrast agent.
  • Na 2 B 12 l 12 is an ionic compound, because of its exceptionally high iodine percent , the osmolality of solutions containing the required amount of iodine ( 32 gm 1/100 cm 3 ) would (ideally) still be less than non- ionic organic iodinated solutions of approximate 1M.
  • a solution of B 12 I 12 2- 2Na + of 0.24M is characterized by an osmolality of 680 mosmol.kg.
  • Solutions of B 12 l 12 2- of lower osmolality than those of the sodium salts can be made, e . g. , utilizing MgB 12 l 12 .
  • Passage of Na 2 B 12 l 12 through an acid ion exchange column may be employed to produce the conjugate acid, (H 3 O + ) 2 B 12 l 12 .xH 2 O , followed by reaction with MgO or MgCO 3 to give MgB 12 l 12 :
  • a 0.21M solution of MgB 12 l 12 ( 90.8% I) contains 32 gm 1/100 cm 3 , and behaves (osmolality-wise ) as a 0.42 M solution of a non-ionic compound.
  • Li 2 B 12 H 12 and Na 2 B 12 H 12 can be made in almost quantitative yield from LiBH 4 or NaBH 4 .
  • B 12 I 12 2 - Salts of B 12 I 12 2 - are readily sterilizable .
  • B 12 I 12 2 - suffers no degradation in H 2 SO 4 at 150 °C, or in 20% aqueous
  • One general approach to derivative synthesis is direct substitution on B 12 H 12 2- followed by modification of the species thus formed (including halogenation).
  • One attractive feature of the derivative chemistry of B 12 H 12 2- is that substitution can bring about a change in net charge, yielding the possibility of preparing (iodinated) polyhedral boron compounds of varying charge.
  • anions e.g., of net -1 charge, neutral species, non-ionic species, and even cations are feasible.
  • Table II The examples shown in Table II above are illustrative of a wide variety of potential halogen-substituted polyhedral boron species . Most have outstanding hydrolytic and oxidative stability, and high halogen content.
  • An exemplary contrast media reagent formulation may for example comprise B 12 I 10 (NH 3 ) 2 .
  • This non-ionic derivative contains close to 89% I and is water-soluble.
  • routes to its preparation There are a number of routes to its preparation.
  • Other preferred reagent species from the foregoing listing include B 12 l 10 (CH 2 NH 3 ) 2 and B 12 I 10 (CH 2 OH) 2 2- .
  • Molecular dimers of the halogenated polyhedral boron compounds may be synthesized to produce radiopaque particles which are larger than normal capillaries fenestration. This limits distribution of the boron compounds to the intravascular space in the use of contrast media formulations containing such boron compounds.
  • Cyclophosphazenes and polyphosphazenes constitute a class of compounds which may be employed as "backbone” or “framework” chemical structures to which active moieties of currently used contrast media agents, as well as active moieties of the above- discussed boron species, may be attached.
  • Cyclophosphazenes such as (Cl 2 PN) 3 , are based on alternating P and N atoms:
  • cyclophosphazenes usefully employed in the broad practice of the present invention have the following formula:
  • R 1 and R 2 may be the same or different, and are
  • organo groups e.g., alkyl, halo
  • n is from 3 to 8; with the proviso that at least one of the R 1 and R 2 groups comprises at least one iodine atom and at least one boron atom, and that the compound is of a radiopaque character.
  • Polyphosphazenes comprise a P-N chain backbone and have the following formula
  • a 1 , and A 2 are end groups which may be of any suitable organic constituency which is compatible with the polyphosphazene and does not preclude its efficacy for radiological imaging purposes -
  • a 1 and A 2 may be the same or different, and may for example comprise alkyl or other hydrocarbyl radicals;
  • R 1 and R 2 may be the same or different, and are independently selected from hydrogen, halo, and organo groups (e.g., alkyl, haloalkyl, aryl, arylalkyl, alkenyl, alkylamino, arylamino, etc.); and
  • n is from 2 to 20,000; with the proviso that at least one of the R 1 and R 2 groups comprises at least one iodine atom and at least one boron atom; and which is of a suitable radiopaque character.
  • the compound ( Cl 2 PN ) 3 is a white , crystalline material prepared from phosphorous pentachloride and ammonium chloride .
  • the P-Cl bonds are highly reactive , reacting readily with nucleophiles such as alkoxides , aryloxides , amines , etc . , to give completely substituted derivatives .
  • the ( Cl 2 PN ) 3 compound may be usefully employed to construct "non-ionic " contrast media agents .
  • a triiodo benzene species could be used to partially derivativatize the (Cl 2 PN) 3 ring, followed by derivatization with appropriate groups to confer aqueous solubility:
  • halogenated boron compounds may be usefully employed to synthesize boron-based contrast media reagents according to the present invention.
  • species such as shown below can be constructed which possess high water solubility and high I content:
  • X is an appropriate linking or bridge moiety, e. g. , an amino or alkoxide linker moiety.
  • the reactive chloride atoms of the starting material in these reactions can be replaced with nucleophiles such as amines, alkoxides, aryloxides, etc.
  • contrast media reagents Of particular interest in the manufacture of contrast media reagents according to the present invention is the synthesis approach of partial substitution of Cl- with triiodinated phenoxide or iodinated B 12 species. The remaining chlorides then can be replaced with substituents to confer water solubility, such as MeNH-, glycerol, etc.
  • the water-soluble polyphosphazene polymers described above desirably contain hydrolyzable groups capable of producing a degradable polymer.
  • an amino acid such as glycine can be attached via a P-N bond. Hydrolysis of the P-N bonded amino acids gives a P-OH bond.
  • the hydrophosphazenes are hydrolytically unstable, decomposing to harmless phosphate and ammonia, thereby permitting a highly iodinated polymeric contrast media reagent to be synthesized with the capability to eventually erode and be excreted from the body.
  • Aqueous solution of B 12 l 12 2- , 2Na + at 0.24M is characterized by an unexpected low viscosity at this iodine concentration of 1.5 mpasc.s at 37°C and low osmolality of 680 mosmol.kg water and high stability with no release of iodide after sterilization.
  • 50 milliliters of the solution are intravenously administered over a period of approximately 60 seconds, using a Coeur® 150 ml angiographic syringe (Coeur Laboratories, Inc., Raleigh, North Carolina, USA) connected by a luer-lock coupling to a catheter which is joined at its opposite end by venous shunt to the vascular administration site.
  • the administration is effected by a Mark V® angiographic power injector (Medrad Corporation, Pittsburgh, Pennsylvania, USA), with the syringe being appropriately positioned in the injector jacket of the automatic injector apparatus. Peak blood values are attained immediately following injection. The blood concentration falls rapidly over the next 5-10 minutes, and equilibration with the extracellular compartments is attained in approximately 10 minutes.
  • the vascular situs is visualized by impingement of an X-ray beam on such situs, from an X-ray generator comprising an X-ray tube with a collimator serving as a beam-limiting device.
  • the X-ray beam has a photon energy of above 20 keV.
  • a radiographi ⁇ image is produced of the vascular situs , and is employed to determine whether occlusion of the vascular lumen has occurred and whether angioplasty is an appropriate therapeutic intervention.
  • the contrast media formulation is excreted rapidly unchanged by renal glomerular filtration.
  • Example X The procedure of Example X is repeated using a contrast media formulation comprising B 12 l 10 (NH 3 ) 2 , and the efficacy of such reagent compound is demonstrated.
  • Example X The procedure of Example X is repeated with various cyclophosphazenes and polyphosphazenes, comprising at least 40% iodine deriving from boroiodide pendent functionality which is bonded directly or indirectly (via an amino or alkoxide divalent linker group) to a phosphorous atom of the reagent, and the efficacy of such reagent compounds is demonstrated.
  • the present invention preferably is carried out with a halogenated derivative of boron having (i) a stability in water sufficiently high to enable it to withstand sterilization conditions, (ii) a molar halogen concentration of at least 40% and lower than 95%, (iii) an osmolality lower than 800 mosmol/kg H 2 O at concentrations higher than 100 g of halogen, and (iv) a low LD 50 mouse toxicity at least equal to 2 g of halogen per kg of body weight of the mouse.
  • a halogenated derivative of boron having (i) a stability in water sufficiently high to enable it to withstand sterilization conditions, (ii) a molar halogen concentration of at least 40% and lower than 95%, (iii) an osmolality lower than 800 mosmol/kg H 2 O at concentrations higher than 100 g of halogen, and (iv) a low LD 50 mouse toxicity at least equal to 2 g of halogen per kg of body
  • a highly preferred class of contrast agents is the class of derivatives of boron of the formula (I) set out hereinabove. including the salts of such derivatives of formula (I), such as salts of meglumine, lysine, arginine, sodium, calcium, N- methyl-glucamine, as hereinabove described.
  • the contrast agent formulations suitably comprise aqueous solutions wherein, when the contrast agent is of formula (I), the concentration of contrast agent is from about 0.2 M to about 0.5 M per liter, wherein the solvent mqdium of the contrast agent formulation preferably is bidistilled water, and wherein the formulation contains conventional-type pharmaceutical composition adjuvants, such as sodium chloride, tris( hydroxymethyl)amine-methane hydrochloride, amine of tris (hydroxymethyl) amino-methane, heparine, sodium citrate and sodium calciedetate.
  • conventional-type pharmaceutical composition adjuvants such as sodium chloride, tris( hydroxymethyl)amine-methane hydrochloride, amine of tris (hydroxymethyl) amino-methane, heparine, sodium citrate and sodium calciedetate.
  • aqueous solutions are preferably administered in doses ranging from about 10 to about 250 ml of aqueous solution containing from about 200 to about 400 g of halogen per liter.
  • Administration may be enterally or parenterally and preferably is oral, rectal, intravenous, intra-articular, intra-arterial, sub-arachnoidal, bronchial, lymphatical, or intra-uterine.
  • the X-ray contrast agent of the invention may be in sub-micron powder form comprising particles preferably less than 400 nm in average particle diameter, suspended in a physiologically compatible solvent as a colloidal suspension.
  • Presently preferred X-ray contrast agent formulations according to the present invention include the N-methylglucamine formulations (a)-(d) set hereinabove, having a pH of from about 6.5 to about 7.5.
  • the X-ray contrast agents preferably are encapsulated within liposomes or associated with biomolecules such as proteins, lipoproteins, glycoproteins, polysaccharides, polypeptides, dextrans, polylysins, albumin, monoclonal and polyclonal antibodies, and dendrimers.
  • the X-ray imaging contrast agents of the invention are usefully employed in biocompatible imaging compositions for the radiological imaging and visualization of corporeal sites, for purpose of diagnosis and treatment of physiological conditions.
  • the imaging compositions are radiopaque in character and thus when administered to a body part or other corporeal site, permit the appertaining body region to be subjected to radiation (X-rays) and fluoroscopic analysis.
  • Radiological imaging applications within the broad scope of the invention include excretory urography, angiocardiography, and aortography. Specific examples include coronary angioplasty determination, wherein the contrast agent formulation is introduced into a coronary lumen, and gynocological imaging wherein the contrast agent formulation is transcervically introduced for radiological visualization of the pelvic region.
  • the X-ray contrast agents, compositions, and methods of the present invention have broad utility in the visualization, diagnosis, and treatment of animal, e.g., mammalian, subjects, particularly humans.

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Abstract

Agent de contraste pour l'imagerie radiologique, constitué d'un dérivé de bore halogéné, en particulier iodé ou bromé, présentant les caractéristiques nécessaires à son utilisation en imagerie radiologique. L'agent de contraste peut être utilisé pour visualiser un site corporel par des techniques radiologiques impliquant l'apport au niveau du site corporel d'une quantité permettant l'imagerie d'une composition physiologiquement acceptable contenant le réactif à base de bore. L'invention concerne également toute une variété de réactifs à base de bore pouvant être utilisés, comprenant des dérivés de bore vectorisés, par exemple des dérivés de bord encapsulés dans des liposomes, fixés sur ou liés à des macromolécules ou des polymères, etc. Les agents de contraste, les compositions et le procédé selon la présente invention peuvent être utilisés dans une large gamme d'applications en imagerie radiologique, par exemple l'urographie avec compression, l'angiocardiographie, l'aortographie, etc.
PCT/US1992/009120 1991-10-23 1992-10-23 Agents et compositions de contraste pour l'imagerie radiologique, et procede d'imagerie radiologique faisant appel a ces compositions et agents Ceased WO1993008122A1 (fr)

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JP5507942A JPH07502991A (ja) 1991-10-23 1992-10-23 放射線撮像用造影剤及び組成物及びそれを用いた放射線撮像法
EP92923022A EP0609374A4 (fr) 1991-10-23 1992-10-23 Agents et compositions de contraste pour l'imagerie radiologique, et procede d'imagerie radiologique faisant appel a ces compositions et agents.
IL103696A IL103696A0 (en) 1992-10-23 1992-11-10 Contrast agents and compositions for radiological imaging,and radiological imaging method utilizing same

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US07/781,812 US5256394A (en) 1991-10-23 1991-10-23 Radiological imaging method, and contrast media reagents therefor
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005202A1 (fr) * 1993-08-16 1995-02-23 University Of Washington Molecules-cages de borane iodees utilisees en tant que moyens de contraste de rayons x
WO1995026354A1 (fr) * 1994-03-25 1995-10-05 Centro Investigacion Justesa Imagen, S.A. Nouveaux composes iodes de bore utiles en tant qu'agents de contraste aux rayons x, et compositions pharmaceutiques les contenant
WO2013021093A1 (fr) 2011-08-10 2013-02-14 Digna Biotech, S.L. Utilisation de la cardiotrophine-1 pour le traitement de maladies rénales

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5455022A (en) * 1993-09-09 1995-10-03 Associated Universities, Inc. Halogenated sulfidohydroboranes for nuclear medicine and boron neutron capture therapy
US5595878A (en) * 1995-06-02 1997-01-21 Boron Biologicals, Inc. Detection of biopolymers and biooligomers with boron hydride labels
US20040175329A1 (en) * 2003-03-07 2004-09-09 Fisher John Steele Method for continuous visualization of a body lumen
DE102006012181B4 (de) * 2006-03-16 2016-03-10 Siemens Aktiengesellschaft Verfahren und Vorrichtung zur getrennten dreidimensionalen Darstellung von Arterien und Venen in einem Körperteil
US10814021B2 (en) 2017-12-15 2020-10-27 University Of Washington Paramagnetic boron-doped graphene quantum dots and their application for safe magnetic resonance imaging

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3045049A (en) * 1959-01-27 1962-07-17 Olin Mathieson Halogen containing organic derivatives of decaborane
GB985706A (en) * 1963-06-25 1965-03-10 Du Pont Boron hydride carbonyl compounds and their preparation
US3287416A (en) * 1960-10-21 1966-11-22 Thiokol Chemical Corp Halogen containing organoboron compounds and method of preparation
DE1229074B (de) * 1963-09-05 1966-11-24 Du Pont Verfahren zur Herstellung von Dodecaboranat-und/bzw. Dodecaboran-thioaetheraten
US3334136A (en) * 1963-07-09 1967-08-01 Du Pont Salts of certain polyhedral polyborates and their preparation
US3376347A (en) * 1964-12-02 1968-04-02 Thiokol Chemical Corp Mono-and di-c-halogenated meta-and paracarborane
US3395182A (en) * 1966-01-24 1968-07-30 Olin Mathieson Carbonyl-o-carboranes and process
US3427136A (en) * 1963-11-19 1969-02-11 Du Pont Diazonium compounds of the decaborate cage radical
US3551120A (en) * 1962-12-21 1970-12-29 Du Pont Substituted dodecaborates
SU479772A1 (ru) * 1973-07-19 1975-08-05 Ордена Ленина Институт Элементоорганических Соединений Ан Ссср Способ получени 2,3-бис-(о-карборанил) -бутадиена
US4288585A (en) * 1980-03-12 1981-09-08 Nasa Carboranylcyclotriphosphazenes and their polymers
US4312989A (en) * 1979-08-21 1982-01-26 The United States Of America As Represented By The Secretary Of The Army Pharmacologically active amine boranes
US4444972A (en) * 1983-05-03 1984-04-24 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Carboranylmethylene-substituted phosphazenes and polymers thereof
US4705849A (en) * 1985-04-15 1987-11-10 E. R. Squibb & Sons, Inc. Boronic acid adducts of technetium-99m dioxime complexes
US5116980A (en) * 1988-01-29 1992-05-26 The United States Of America As Represented By The United States Department Of Energy Boron containing compounds and their preparation and use in neutron capture therapy
US5130302A (en) * 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5177198A (en) * 1989-11-30 1993-01-05 University Of N.C. At Chapel Hill Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314990A (en) * 1961-09-28 1967-04-18 Du Pont Sulfur-containing boron compounds
US4412053A (en) * 1981-02-09 1983-10-25 Neilson Robert H Polyphosphazene compounds and method of preparation
US4523009A (en) * 1981-02-09 1985-06-11 Neilson Robert H Polyphosphazene compounds and method of preparation
DE3118962A1 (de) * 1981-05-13 1982-12-09 Hoechst Ag, 6000 Frankfurt Durch piperidylgruppen substituierte phophazene, verfahren zu ihrer herstellung, ihre verwendung als stabilisatoren und die mit ihnen stabilisierten polymermassen
US4971897A (en) * 1989-02-03 1990-11-20 Eastman Kodak Company Photographic silver halide element containing cyclic phosphazene and salt antistatic composition
CA2034042C (fr) * 1990-01-18 1999-08-17 Adrian D. Nunn Produits d'addition de l'acide boronique et de complexes rhenium-dioxime et technetium-99m-dioxime, contenant un groupe a activite biochimique

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3045049A (en) * 1959-01-27 1962-07-17 Olin Mathieson Halogen containing organic derivatives of decaborane
US3287416A (en) * 1960-10-21 1966-11-22 Thiokol Chemical Corp Halogen containing organoboron compounds and method of preparation
US3551120A (en) * 1962-12-21 1970-12-29 Du Pont Substituted dodecaborates
GB985706A (en) * 1963-06-25 1965-03-10 Du Pont Boron hydride carbonyl compounds and their preparation
US3334136A (en) * 1963-07-09 1967-08-01 Du Pont Salts of certain polyhedral polyborates and their preparation
DE1229074B (de) * 1963-09-05 1966-11-24 Du Pont Verfahren zur Herstellung von Dodecaboranat-und/bzw. Dodecaboran-thioaetheraten
US3427136A (en) * 1963-11-19 1969-02-11 Du Pont Diazonium compounds of the decaborate cage radical
US3376347A (en) * 1964-12-02 1968-04-02 Thiokol Chemical Corp Mono-and di-c-halogenated meta-and paracarborane
US3395182A (en) * 1966-01-24 1968-07-30 Olin Mathieson Carbonyl-o-carboranes and process
SU479772A1 (ru) * 1973-07-19 1975-08-05 Ордена Ленина Институт Элементоорганических Соединений Ан Ссср Способ получени 2,3-бис-(о-карборанил) -бутадиена
US4312989A (en) * 1979-08-21 1982-01-26 The United States Of America As Represented By The Secretary Of The Army Pharmacologically active amine boranes
US4368194A (en) * 1979-08-21 1983-01-11 The United States Of America As Represented By The Secretary Of The Army Pharmacologically active amine boranes
US4288585A (en) * 1980-03-12 1981-09-08 Nasa Carboranylcyclotriphosphazenes and their polymers
US4444972A (en) * 1983-05-03 1984-04-24 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Carboranylmethylene-substituted phosphazenes and polymers thereof
US4705849A (en) * 1985-04-15 1987-11-10 E. R. Squibb & Sons, Inc. Boronic acid adducts of technetium-99m dioxime complexes
US5116980A (en) * 1988-01-29 1992-05-26 The United States Of America As Represented By The United States Department Of Energy Boron containing compounds and their preparation and use in neutron capture therapy
US5177198A (en) * 1989-11-30 1993-01-05 University Of N.C. At Chapel Hill Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates
US5130302A (en) * 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
Anal. Chem., Vol. 59(8), 15 April 1987, UNGER et al., "Comparison of Desorption Ionization Methods for the Analysis of Neutral Seven-Coordinate Technetion Radio Pharmaceuticals", pages 1145-49, see entire document. *
CHEMICAL ABSTRACTS, Vol. 114, No. 23, issued 10 June 1991, ISHIWATA et al., "Synthesis and Radiation Dosimetry of 4-Borono-2 (18F) fluoro-DL-phenylalanine: A Target Compound for PET and Boron Neutron Capture Therapy", see page 412, Abstract No. 224582b, Appl. Radiat. Isot., 42(2), 325-28 (1991). *
CHEMICAL ABSTRACTS, Vol. 116, No. 1, issued 06 January 1992, ISHIWATA et al., "4-Borono-2-(18F) fluoro-DL-phenylalanine as a Target Compound for Boron Neutron Capture Therapy: Tumor Imaging Potential with Positron Emissiar Tomography", see page 293, Abstract No. 2906n, Nucl. Med. Biol., 18(7), 745-51 (1991). *
Inorg. Chim. Acta, Vol. 186, No. 1, issued 01 August 1991, MOBASHAR et al., "New Routes to Mercaptoacetyloeotide Ligand Precursors Utilizing Carboxy Terminus Pentaamminecbalt (III) Protection", pages 139-47, see entire document. *
Inorganic Chemistry, Vol. 3, No. 10, issued 29 September 1964, HANSIJUERGEN et al., "Perchlorocerborane and Perchlorocerborane", pages 1464-5, see entire document. *
Inorganic Chemistry, Vol. 3, No. 2, issued 27 January 1964, KNOTH et al., "Chemistry of Boranes. IX. Halogenation of B10H10-2 and B12H12-2", pages 159-67, see entire document. *
Inorganic Chemistry, Vol. 3, No. 8, issued 29 July 1964, MILLER et al., "Chemistry of Boranes. XVI. A New Heterocyclic Boron Compound", pages 1196-97, see entire document. *
Inorganic Chemistry, Vol. 8, No. 10, issued October 1969, CENTOFANTI et al., "Fluorophosphine Ligands. VII. Difluorophosphine Adducts with Tetraborane-8", pages 2072-74, see entire document. *
Inorganic Chemistry, Vol. 8, No. 10, October 1969, WIERSEMA et al., "Electrochemical Preparation and Halogenation of 1,1'-u- Hydro-bis (undecahydro-closododecaborate (3-),B24H233-", pages 2074-70, see entire document. *
J. Am. Chem. Soc., Vol. 86, No. 1, issued 05 January 1964, KNOTH et al., "Diazonium and Carbonyl Derivatives of Polyhedral Bosanes", pages 115-16, see entire document. *
Journal of Labelled Compounds and Radio Pharmaceuticals, Vol. XXIII, No. 8, issued August 1986, PARIKH et al., "Synthesis and Biodistribution of Radioiodinated Selenonium Salts: Potential Myocardial Imaging Agents", pages 815-24, see entire document. *
See also references of EP0609374A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005202A1 (fr) * 1993-08-16 1995-02-23 University Of Washington Molecules-cages de borane iodees utilisees en tant que moyens de contraste de rayons x
US5489673A (en) * 1993-08-16 1996-02-06 University Of Washington Iodinated borane cage molecules as X-ray contrast media
US5679322A (en) * 1993-08-16 1997-10-21 University Of Washington Iodinated borane cage molecules as X-ray contrast media
WO1995026354A1 (fr) * 1994-03-25 1995-10-05 Centro Investigacion Justesa Imagen, S.A. Nouveaux composes iodes de bore utiles en tant qu'agents de contraste aux rayons x, et compositions pharmaceutiques les contenant
WO1995026353A1 (fr) * 1994-03-25 1995-10-05 Centro Investigacion Justesa Imagen, S.A. Nouveaux composes iodes de bore utiles en tant qu'agents de contraste aux rayons x, et compositions pharmaceutiques les contenant
WO2013021093A1 (fr) 2011-08-10 2013-02-14 Digna Biotech, S.L. Utilisation de la cardiotrophine-1 pour le traitement de maladies rénales

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AU2908092A (en) 1993-05-21
JPH07502991A (ja) 1995-03-30
EP0609374A4 (fr) 1996-07-10

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